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学科主题: 基础医学
题名:
N-methylpurine DNA glycosylase inhibits p53-mediated cell cycle arrest and coordinates with p53 to determine sensitivity to alkylating agents
作者: Song, Shanshan1,2,3,4; Xing, Guichun3,4; Yuan, Lin3,4; Wang, Jian3,4; Wang, Shan3,4; Yin, Yuxin5; Tian, Chunyan3,4; He, Fuchu1,2,3,4; Zhang, Lingqiang3,4
关键词: MPG ; p53 ; cell cycle arrest ; base excision repair ; alkylating agents
刊名: CELL RESEARCH
发表日期: 2012-08-01
DOI: 10.1038/cr.2012.107
卷: 22, 期:8, 页:1285-1303
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Cell Biology
研究领域[WOS]: Cell Biology
关键词[WOS]: BASE EXCISION-REPAIR ; MICROSATELLITE INSTABILITY ; CHRONIC INFLAMMATION ; METHYLATING AGENTS ; COMET ASSAY ; DAMAGE ; BINDING ; PROTEIN ; MECHANISMS ; GENES
英文摘要:

Alkylating agents induce genome-wide base damage, which is repaired mainly by N-methylpurine DNA glycosylase (MPG). An elevated expression of MPG in certain types of tumor cells confers higher sensitivity to alkylation agents because MPG-induced apurinic/apyrimidic (AP) sites trigger more strand breaks. However, the determinant of drug sensitivity or insensitivity still remains unclear. Here, we report that the p53 status coordinates with MPG to play a pivotal role in such process. MPG expression is positive in breast, lung and colon cancers (38.7%, 43.4% and 25.3%, respectively) but negative in all adjacent normal tissues. MPG directly binds to the tumor suppressor p53 and represses p53 activity in unstressed cells. The overexpression of MPG reduced, whereas depletion of MPG increased, the expression levels of pro-arrest gene downstream of p53 including p21, 14-3-3 sigma and Gadd45 but not pro-apoptotic ones. The N-terminal region of MPG was specifically required for the interaction with the DNA binding domain of p53. Upon DNA alkylation stress, in p53 wild-type tumor cells, p53 dissociated from MPG and induced cell growth arrest. Then, AP sites were repaired efficiently, which led to insensitivity to alkylating agents. By contrast, in p53-mutated cells, the AP sites were repaired with low efficacy. To our knowledge, this is the first direct evidence to show that a DNA repair enzyme functions as a selective regulator of p53, and these findings provide new insights into the functional linkage between MPG and p53 in cancer therapy.

语种: 英语
所属项目编号: 2011CB910802 ; 2012CB910702 ; 2010CB912202 ; 31071144 ; 31125010
项目资助者: National Basic Research Programs ; National Natural Science Foundation
WOS记录号: WOS:000307119500012
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/67228
Appears in Collections:基础医学院_病理学系_期刊论文

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作者单位: 1.Chinese Acad Med Sci, Dept Med Genet, Inst Basic Med Sci, Beijing 100005, Peoples R China
2.Peking Union Med Coll, Beijing 100005, Peoples R China
3.Beijing Inst Radiat Med, State Key Lab Prote, Beijing Proteome Res Ctr, Beijing 100850, Peoples R China
4.Peking Univ, Dept Pathol, Sch Basic Med Sci, Beijing 100191, Peoples R China
5.Natl Engn Res Ctr Prot Drugs, Beijing 100850, Peoples R China

Recommended Citation:
Song, Shanshan,Xing, Guichun,Yuan, Lin,et al. N-methylpurine DNA glycosylase inhibits p53-mediated cell cycle arrest and coordinates with p53 to determine sensitivity to alkylating agents[J]. CELL RESEARCH,2012,22(8):1285-1303.
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